Investigation and management of the solitary pulmonary nodule · measurement of nodule size and characterisation of morphology, in particular the identification of ground-glass opacities

s36 © Royal College of Physicians, 2013. All rights reserved.

■ RESPIRATORY MEDICINE Clinical Medicine 2013, Vol 13, No 6: s36–s40

ABSTRACT – With the advent of multi-detector computed tomography, the identification of solitary pulmonary nod-ules is becoming ever more common. Although the preva-lence of malignancy in a high risk population is only 1–1.5%, accurate identification of malignant nodules is essential to allow optimal treatment. In this article we review the most common causes of solitary pulmonary nodules and discuss diagnostic algorithms as well as some of the novel diagnostic imaging techniques in development.

KEY WORDS: Solitary pulmonary nodule, lung cancer, com-puted tomography, lung cancer screening

Background

The incidental finding of a solitary pulmonary nodule (SPN) is

taking increasing prominence in the workload of both radiologists

and respiratory physicians. The introduction of helical computed

tomography (CT) during the 1990s and, more recently, multide-

tector row CT, which can generate 1–2-mm thick slices, has ena-

bled the identification of ever smaller subcentimetre nodules.

Prevalence rates of pulmonary nodules have been reported mainly

in the context of lung cancer-screening trials and vary widely from

8% to 51%,1,2 depending upon the population studied. In addition,

approximately 10% of individuals will develop a new nodule over

a 1-year period.3 Whereas up to half of all smokers over the age of

50 years will have at least one nodule,4 the prevalence of lung

cancer in a high-risk population is only approximately 1–1.5%.2

Lung cancer is the leading cause of cancer deaths worldwide.2

The overall 5-year survival rate of patients with lung cancer

across Europe is only 10% because of the large percentage of

patients presenting with locally advanced or metastatic disease.2

This contrasts sharply with the good surgical outcomes for stage

1a (tumour size <2 cm) non-small cell lung cancer with post-

operative 5-year survival approaching 80%.1,5 Therefore,

balancing the need for identifying an early-stage lung cancer with

the risk of over-investigation and/or -radiation exposure and

provoking undue anxiety in patients with benign lesions is piv-

otal in the diagnostic evaluation and management of the SPN.

Definition

A pulmonary nodule is a round or oval lesion, 3 cm or less in

diameter, of soft-tissue density that is completely surrounded by,

and obliterates, the underlying lung parenchyma.6 The 3-cm cut

off is arbitrary because lung nodules were originally described on

chest radiographs as pulmonary opacities 1–3 cm in diameter.6,7

The advent of thin-slice spiral CT has allowed more accurate

measurement of nodule size and characterisation of morphology,

in particular the identification of ground-glass opacities. These are

intrapulmonary nodules, with a solid component of <5% of the

nodule volume, that do not attenuate the architecture of the

underlying lung parenchyma.8 The term ‘subsolid nodule’ is inter-

changeable with ground-glass nodule (GGN) when the latter

encompasses discrete pulmonary nodules that are either of pure

ground-glass or have part-solid attenuation (Fig 1).8

Differential diagnosis

The differential diagnosis of an incidental SPN encompasses up

to 80 different conditions.7 The probable diagnosis in any given

scenario is influenced by the individual’s age, smoking history,

history of occupational exposures and other risk factors for

malignancy, as well as country of residence.7 Some of the infec-

tious, non-infectious and neoplastic causes of an SPN are listed

in Table 1. In the absence of any other CT features, the likelihood

of a SPN being a metastasis from an extrapulmonary malignancy

Investigation and management of the solitary pulmonary nodule

Rawya Ahmed, Nagmi R Qureshi and Robert C Rintoul

Rawya Ahmed, specialty trainee in respiratory medicine, Eastern

Deanery; Nagmi R Qureshi, consultant cardiothoracic radiologist;

Robert C Rintoul, consultant respiratory physician

Papworth Hospital, Cambridge, UK Fig 1. Part-solid, part ground-glass nodule.

CMJ1306-s36-s40-Rintoul.indd 36CMJ1306-s36-s40-Rintoul.indd 36 11/21/13 9:53:49 PM11/21/13 9:53:49 PM


© Royal College of Physicians, 2013. All rights reserved. s37

mately 21–400 days.6 Faster volume-doubling times of <20 days

or slower growth rates of >400 days are more likely to reflect

infectious or benign aetiologies, respectively.9 Stability of growth

over 2 years implies a doubling time of more than 730 days;6 it

was previous conventional wisdom that this stability reflected a

benign aetiology.6,10 It is now recognised that GGNs might reflect

slow-growing adenocarcinoma and their stability over 2 years

reduces, but does not eliminate, the likelihood of malignancy.9

The best predictors for a nodule being benign are chronicity

and patterns of calcification.10 Previous imaging, if available,

rather than a bronchogenic carcinoma varies according to the

site of the original primary.9,10 It is more likely in cases of

melanoma, sarcoma or testicular carcinoma, but less likely if the

primary is a head and neck cancer, or originating from the upper

gastrointestinal tract, bladder, cervix or prostate.9

Nodule morphology and growth as a predictor of aetiology

The SPN is often an incidental finding in an asymptomatic indi-

vidual. Most malignant nodules have doubling times of approxi-

Table 1. Causes of a solitary pulmonary nodule.

Cause Features that might help support a diagnosis

Malignant neoplasm

Primary bronchogenic carcinoma Risk factors for lung cancer

Lymphoma Mediastinal or extrapulmonary lymphadenopathy; presence of B symptoms should be sought

Solitary metastasis (spread commonly from skin, head and neck, thyroid, breast, upper gastrointestinal tract, colon, ovaries, prostate, testes and skin sarcomas)

History of current and/or previous cancer of corresponding site

Carcinoid Smooth, well-defined edges, low attenuation on contrast-enhanced CT, but negative on PET

Non-infectious cause

Hamartoma Smooth well-defined edges, fat content or chondroid ‘popcorn’ pattern of calcification

Intrapulmonary lymph node Usually below the carina, subpleural or close to fissure, half-moon or polygonal in shape

Rounded atelectasis Basal, subpleural, whorl appearance

Intrapulmonary haematoma Present following recent thoracic and/or pleural procedure or intercostal chest drain insertion

Mucoid impaction Previous radiology demonstrating mucocele or bronchial atresia in corresponding region

Infected bulla History of emphysema

Infection and/or inflammation

TB and/or atypical mycobacteria Previous history of TB or presence of calcified lymph nodes; immune-compromised state

Aspergillus fumigatus Chronic lung disease; immune-compromised state

Histoplasmosis Current and/or previous residence of, or travel to, North, Central and South America

Coccidiomycosis Current and/or previous residence of, or travel to, southwestern USA

Ecchinomycosis Current and/or previous residence of, or travel to, sheep- and cattle-raising regions of the Mediterranean and Asia

Dirofilariasis Parasitic infection caused by dog heartworm, common in North America and southern Europe

Round pneumonia Pneumococcus infection

Sarcoidosis Extrapulmonary manifestations of sarcoidosis, other lung parenchymal features and mediastinal lymphadenopathy

Rheumatoid lung nodule Seropositive rheumatoid arthritis, presence of skin rheumatoid nodules

Granulomatosis with polyangiitis (Wegner’s granulomatosis)

Symptoms and extrapulmonary features suggestive of vasculitis

Benign neoplasm

Chondroma

Lipoma Low attenuation on contrast-enhanced CT, fat content

Fibroma

Neural tumour (eg neurofibroma or schwannoma) Features of neurofibromatosis

Congenital causes

Pulmonary sequestration Visible feeding vessel directly from systemic circulation

Bronchogenic cyst

CT = computerised tomography; PET = positron emission tomography; TB = tuberculosis.




might provide valuable information about chronicity and aeti-

ology. Hamartomas can exhibit chondroid or ‘popcorn-like’

calcification (Fig 2). A wholly calcified nodule is likely to be an

old granuloma, as are nodules with central or laminated

calcification patterns.6 By contrast, eccentric or peripheral calci-

fication can imply a carcinoma that has engulfed an adjacent

calcified granuloma and this should raise suspicion of a

malignant process.1

Other morphological characteristics, such as nodule mar-

gins, cavitation and wall thickness and the presence of satellite

nodules, do not enable distinction between benign and

malignant nodules.6 Spicules and lobulated margins can repre-

sent irregular interstitial fibrosis or infiltrative tumour growth

(Fig 3).9,11 Although the presence of lobulated or spiculated

margins increases the likelihood of malignancy, it is not a pre-

requisite, because one in five nodules with smooth margins is

malignant.1,6 It is now recognised that some indeterminant

subpleural or intraparenchymal nodules represent intra-

pulmonary lymph nodes (IPLNs).12 Ranging in size between 3

and 10 mm, IPLNs can wax and wane in size, confusing the

unwary and leading to repeat CT for an otherwise ‘normal’

structure. Confident diagnosis by an experienced thoracic

radiologist, based on location and morphology, can often avoid

unnecessary patient anxiety.

Evaluating the growth rate of an SPN can be difficult and is

dependent upon its size. For a spherical nodule, a doubling of its

volume results in only a 26–30% increase in its diameter.8,10

Accurately and reproducibly measuring a 1-mm increase in diam-

eter of a 4-mm nodule is harder than for a 3-cm mass. A 1-mm

increase in diameter of a 4-mm nodule represents a doubling in

volume1 that, if occurring during a certain time frame, increases

the likelihood of malignancy. However, this can be easily over-

looked given intra- and inter-observer variation in nodule size

measurements, particularly in the presence of spiculated margins.

In the context of lung-screening trials, up to one in five posi-

tive-screening CT scans at baseline were the result of part-solid

or non-solid GGNs.8 Such lesions are associated with higher

rates of malignancy, with adenocarcinoma being the most

common subtype.8,11 The previously used term ‘bronchiolo-

alveolar carcinoma’ has recently been reclassified in a continuum

of pre-invasive to overtly malignant subtypes, with atypical

adenomatous hyperplasia being a premalignant subtype and

adenocarcinoma in situ and minimally invasive adenocarcinoma

describing lesions with lepidic growth patterns, with and without

invasive features, respectively.13 Invasive adenocarcinoma is fur-

ther subdivided according to growth patterns.13

Risk assessment

The diagnostic approach to the incidental SPN should include

a thorough assessment of the individual with a full history

and physical examination, with particular attention paid to

factors increasing cancer risk. In addition to routinely identi-

fied risk factors for lung cancer, such as age, active and passive

smoking history and occupational exposure to carcinogens,

including asbestos, other risk factors should not be over-

looked. Previous history of cancer of any type as well as

exposure to radiotherapy, cancer in a first-degree relative and

lung parenchymal abnormalities, such as chronic obstructive

pulmonary disease and interstitial pulmonary fibrosis, should

be recorded.

The probability of a nodule being malignant increases with

age, being <3% in under-40-year olds, but 50% in those over 60

years of age.1 Furthermore, the prevalence of malignancy

increases with nodule size and is estimated from lung cancer-

screening study data to be <1% in nodules <5 mm in diameter,

and >80% in those larger than 2 cm.1 Hence, evaluating an SPN

in the context of a patient’s age and other risk factors, along with

its size, enables a quanitative assessment of lung cancer risk and

guides the management approach.

Quantitative risk assessment of lung cancer was originally

proposed during the 1970s, using Bayesian analysis,7 and has

been advocated again recently.14 Various mathematical models

exist using a combination of the individual’s characteristics (eg

age, smoking history and previous history of cancer) and fea-

tures of the SPN (eg nodule size and location, and presence of

spiculations) to compute a likelihood ratio of cancer.14,15 Patel et

al argue that a pre-test probability calculation improves risk

stratification and facilitates further management along Fleischner

Society guidelines.14

Diagnostic algorithm

CT is the modality of choice for the initial diagnosis and followup

of pulmonary nodules. Contrast-enhanced CT enables identifica-

tion of parenchymal abnormalities as well as staging of the medi-

astinum and extrapulmonary structures. Unenhanced low-dose

thin-slice multidetector row CT is best utilised for characterising

nodule morphology and assessing growth on followup.

Fig 2. ‘Popcorn’ pattern calcification within a hamartoma in an unenhanced computer tomograph scan of chest.



© Royal College of Physicians, 2013. All rights reserved. s39

Fig 3. Spiculated pulmonary nodule that is highly suggestive of malignancy.

from malignant nodules in a retrospective case series with a

sensitivity and specificity of 91% and 90%, respectively.17

Nodule volume measurements and volume-doubling time esti-

mation using CT volumetric software is currently being utilised

in the UK Lung Screen (UKLS) and the Dutch-Belgian (NELSON)

lung cancer screening trials, comparing low-dose CT with usual

care in those at higher risk of lung cancer.18,19

The degree of contrast enhancement of a nodule depends upon

its vascularity, with correlation between nodule vascular endothe-

lial growth factor expression and microvessel density and uptake

of intravenous contrast medium.6,20 Administration of contrast

followed by serial image acquisition at 60-s intervals for 4 min

enables the measurement of nodule enhancement at fixed time

intervals and the calculation of net enhancement values. A

nodule demonstrating an increase of 15 Hounsfield units (HU)

or less after injection of contrast is likely to be benign, whereas an

increase of >30 HU suggests malignancy.21 A cut-off value of 15

HU has a high sensitivity (98%), reducing false negative rates, but

limited specificity (58%), with an overlap in enhancement pat-

terns and attenuation values between benign and malignant

lesions. The utility of dynamic contrast-enhanced CT is being

investigated in the current UK-based Solitary Pulmonary Nodule

Investigation trial (SPUtNIk).22 This study also includes health

economic modelling for the evaluation of SPNs.

Dynamic contrast-enhanced magnetic resonance imaging

(MRI) is emerging as a tool with better sensitivity and specificity

than CT or PET in distinguishing malignant from benign nod-

ules, in particular those associated with active inflammation.9,23

Investigators have studied different aspects of this technique,

with some looking at the initial first pass of contrast via the arte-

rial system, whereas others have analysed the arterial inflow and

subsequent diffusion and redistribution of contrast into the

Positron emission tomography (PET) uses a positron-emitting

radionuclide isotope of fluorine attached to a glucose analogue

(18F-fluorodeoxyglucose [FDG]) that is avidly taken up by

tissue with high metabolic activity. Combining PET with CT

enables better anatomical correlation of parenchymal abnor-

mality on CT with areas of high metabolic activity on PET, as

well as assessment of the mediastinum for the purposes of

staging. Sensitivity and specificity values of combined PET-CT

have been shown by several studies to be superior to those for

PET or CT alone, and have been reported to be as high as 96%

and 88%, respectively, with a negative predictive value of 92%.9

FDG uptake is influenced by tumour size and metabolic activity

and, thus, PET has a limited role in the diagnostic assessment of

small (<8–10 mm) or purely GGNs.9,16

The approach to the management of the incidental solid SPN

should follow Fleischner Society guidelines,4 outlined in Table 2.

These propose surveillance CT scan followup at set intervals

based on nodule size (mean of length and width) and the indi-

vidual’s risk factors for malignancy; the low-risk group being

those with no or minimal smoking history and no risk factors

for malignancy. The guidelines are not applicable to those sus-

pected of having infection, undergoing CT as part of staging for

known or suspected carcinoma of any site, or those under the

age of 35 years.

Fleischner Society recommendations have recently been pro-

duced for the management of subsolid nodules.13 All individuals

are considered equally without risk stratification and subsolid

nodules are assessed depending on their type and multiplicity.

When assessing multiple nodules, the recommendations are

based on the features of the dominant lesion. It is worth noting

that these recommendations are based on low-dose thin-slice

(1-mm) CT scans reconstructed with appropriate windows for

the solid and non-solid components, with measurements per-

formed across two dimensions and growth assessed against the

original baseline CT. Pure GGNs ≤5 mm do not require followup

if solitary, provided it is confirmed that they have no solid com-

ponent on thin-slice CT. If multiple, interval scans at 2 and 4

years are recommended, as well as investigations to rule out other

causes of multiple GGNs. If >5 mm, pure GGNs, whether solitary

or multiple, require an initial scan at 3 months to confirm persist-

ence and then annual CT scans for a minimum of 3 years. Solitary

part-solid GGNs require initial CT scans at 3 months and, if per-

sistent and with a solid component of <5 mm, can be followed

annually. Part-solid GGNs with a solid component >5 mm

should be considered for biopsy or surgical resection.

Novel diagnostic imaging techniques

Several imaging techniques to better enable differentiation

between benign and malignant lesions are being evaluated.

Nodule growth can be estimated from volumetric measurements

and prediction about likelihood of malignancy inferred from

calculation of volume-doubling time. Using a volume-doubling

time of 500 days as the upper limit for malignancy, but excluding

GGNs, Revel et al proposed a strategy to differentiate benign




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the management of subsolid pulmonary nodules detected at CT: A

statement from the Fleischner Society. Radiology 2013;266:304–17.

Patel VK, Naik SK, Naidich DP 14 et al. A practical algorithmic approach

to the diagnosis and management of solitary pulmonary nodules: Part

2: Pretest probability and algorithm. Chest 2013;143:840–6.

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nodules. Am J Roentgenol 2006;187:135–42.

Baldwin DR, Duffy SW, Wald NJ 18 et al. UK Lung Screen (UKLS) nodule

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2011;66:308–13.

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Yi CA, Lee KS, Kim EA 20 et al. Solitary pulmonary nodules: dynamic

enhanced multi-detector row CT study and comparison with vascular

endothelial growth factor and microvessel density. Radiology

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Address for correspondence: Dr RC Rintoul, Department of Thoracic Oncology, Papworth Hospital, NHS Foundation Trust, Papworth Everard, Cambridge CB23 3RE.Email: [email protected]

interstitial space. Distinct patterns of contrast uptake and

washout demonstrated in malignant and benign inflammatory

nodules have been attributed to differences in nodule micro-

vasculature architecture.23

Summary

The SPN poses a diagnostic challenge that requires careful

clinical–radiological correlation by an expert multidisciplinary

team to avoid over-investigation of benign lesions, while

improving lung cancer survival through detection of early-stage

disease amenable to surgical resection. At present, the Fleischner

guidelines form the backbone for nodule management, although

novel imaging techniques might enable further refinement to

this approach in the future.

References

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of patients with pulmonary nodules: when is it lung cancer? Chest

2007;132:94S–107S.

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2013;23:129–40.

Pastorino U, Bellomi M, Landoni C. Early lung cancer detection with 3

spiral CT and positron emission tomography in heavy smokers: 2 year

results. Lancet 2003;362:593–97.

Table 2. Fleischner Society guidelines for CT surveillance of incidental solitary pulmonary nodules.

Nodule size* (mm)

CT interval periods from baseline scan (if no change in nodule size)

Low-risk individual†

≤4 mm None required

>4–6 mm 12 months then discharge if remains stable

>6–8 mm 6–9 months, 18–24 months, then discharge

>8 mm Consider further evaluation with contrast-enhanced CT scan, PET-CT and biopsy; otherwise surveillance at 3, 9 and 24 months

High-risk individual†

≤4 mm 12 months then discharge if no change in nodule size

>4–6 mm 6–9 months, 18–24 months, then discharge if no change

>6–8 mm 3–6 months, 9–12 months, 24 months, then discharge if no change

>8 mm Consider further evaluation with contrast-enhanced CT scan, PET-CT and biopsy; otherwise surveillance at 3, 9 and 24 months

*Size is a mean of 2 axial measurements (length and width).†Risk is categorised as low if there is no or minimal history of smoking and no other risk factors for malignancy. High-risk individuals have a history of smoking and/or other risk factors for malignancy.

CT = computerised tomography; PET = positron emission tomography.


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Investigation and management of the solitary pulmonary nodule · measurement of nodule size and characterisation of morphology, in particular the identification of ground-glass opacities